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Mar. Drugs 2015, 13(1), 460-492; doi:10.3390/md13010460

Synthesis and Antiproliferative Activity of Thiazolyl-bis-pyrrolo[2,3-b]pyridines and Indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, Nortopsentin Analogues

Biological, Chemical and Pharmaceutical Sciences and Technologies Department, STEBICEF, Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy
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Author to whom correspondence should be addressed.
Academic Editor: Yoshihide Usami
Received: 14 November 2014 / Accepted: 4 January 2015 / Published: 16 January 2015
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
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Abstract

Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase. View Full-Text
Keywords: marine alkaloids; bis-indolyl alkaloids; nortopsentins; thiazolyl-bis-pyrrolo [2,3-b]pyridines; indolyl-thiazolyl-pyrrolo[2,3-c]pyridines; apoptosis; autophagic death; antiproliferative activity marine alkaloids; bis-indolyl alkaloids; nortopsentins; thiazolyl-bis-pyrrolo [2,3-b]pyridines; indolyl-thiazolyl-pyrrolo[2,3-c]pyridines; apoptosis; autophagic death; antiproliferative activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Carbone, A.; Parrino, B.; Vita, G.D.; Attanzio, A.; Spanò, V.; Montalbano, A.; Barraja, P.; Tesoriere, L.; Livrea, M.A.; Diana, P.; Cirrincione, G. Synthesis and Antiproliferative Activity of Thiazolyl-bis-pyrrolo[2,3-b]pyridines and Indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, Nortopsentin Analogues. Mar. Drugs 2015, 13, 460-492.

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